Throughout this application various references are referred to within parentheses. Disclosures of these publications in their entirety are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citations for these references maybe found at the end of this application, immediately preceding the claims.
Paraneoplastic cerebellar degeneration (PCD) is a disorder of the cerebellum found in association with neoplasms usually of lung, ovary, breast, or Hodgkins disease. [1] Neuropathological analysis of the affected brains has revealed extensive loss of Purkinje cells, variable loss of granule and basket neurons and proliferation of Bergman glia. [2] The mechanistic relationship between the primary tumor and the resultant cerebellar dysfunction is not clearly understood. The presence of infiltrating lymphocytes in some of the affected brain has suggested an immune mechanism. [3]
A clinically definable subset of patients with paraneoplastic cerebellar degeneration harbor a characteristic antibody which has been called anti-Yo [4]. These sera react with antigens expressed in the Purkinje cells of the normal cerebellum and in the tumor tissue of the affected individual [5]. There is also evidence of increased antibody synthesis in the affected brain. [6]
These observations suggest a model for the neurological dysfunction in which an immune response primarily directed against a tumor antigen is misdirected against similar antigens peculiar to the cerebellum. On Western blot analysis of Purkinje cells and tumor tissue, the anti-Yo sera react with at least two antigens, a major species of 62 kd (CDR 62) and a minor species of 34 kd (CDR 34). [7] Anti-Yo antibody has been detected in patients prior to discovery of the tumor. [19] In four of these patients, prior radiological investigations had disclosed minor abnormalities of uncertain significance. Detection of this antibody prompted surgical exploration and biopsy disclosed a tumor in each case.
The gene encoding the minor antigen (CDR 34) has been isolated and characterized [8,9]. In addition, a cDNA encoding a 52-kd protein has been isolated, recognized by an antineuronal cell antibody in serum from a patient with PCD associated with uterine carcinoma. [18] However, specificity of reaction between the protein encoded by this isolated cDNA and Yo sera was not established. [18]